Synthesis of the Related Substances of Rosuvastatin / 中国药学杂志

ABSTRACT

OBJECTIVE: To synthesize three related substances of rosuvastatin and establish its standard quality control system. METHODS: t-Butyl-6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropanyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate (1a) was converted into the de-ketal compound 1b, then the latter underwent hydrolysis to get 1c. Finally, N-[4-(4-fluorophenyl)-6-isopropanyl-5-[(1E)-2-[(2S, 4R)-4-hydroxyl-6-oxo-2H-pyran-2-ethenyl]-2-pyrimidinyl]-N-methyl methane sulfonamide (impurity 1) was obtained through intramolecular dehydration. Meanwhile, (3R, 5S, 6E)-7-[4-(4-fluoropheny-1)-6-isopropanyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic acid (impurity 2) was prepared from compound 1b via oxidation with DDQ, reduction with tetramethylammonium triacetoxyborohydride, followed by hydrolysis. (3R, 6E)-7-[4-(4-fluorophenyl)-6-isopropanyl-2-[methyl(methylsulfonyl) amino]-5-pyrimidinyl]-3-hydroxy-5-oxo-6-heptenoic acid (impurity 3) was synthesized through oxidation of compound 1c with DDQ. RESULTS: The structures of three impurities were confirmed by 1H-NMR and MS. CONCLUSION: The synthesized three target compounds can be used as references for the quality control of rosuvastatin calcium.